0 Preface
Bladder cancer is one of the most common malignant tumors of the urinary tract, and its incidence has increased significantly in recent years. Bladder cancer has a clear “multicentric occurrence”, recurrence is very common (about 50%), and 10%-15% of superficial bladder cancers eventually develop into muscle-invasive bladder cancer or metastases, especially in patients with advanced bladder tumors who lack effective treatment [1]. Postoperative bladder perfusion chemotherapy for early bladder cancer is effective in preventing recurrence, but the recurrence rate is still as high as about 20% [2]. Therefore, exploring powerful measures for the treatment of advanced bladder cancer and effective prevention of postoperative recurrence has been the focus of research in urological oncology, especially targeted therapy has become a worldwide research hotspot.
1. Photodynamic therapy
The so-called photodynamics is a photosensitization, an intracellular reaction process in which a specific substance is irradiated by light and causes an increase in the amount of this substance contained.Oscar Raab described the killing effect of light combined with acridines on C. gramineus, a phenomenon described as photodynamic therapy or photochemical toxic effects [3, 4]. In medicine, photodynamics can be used not only for diagnosis (photodynamicdiagnosis, PDD) but also more often for treatment (photodynamictherapy, PDT).PDT was first used by Kelly et al [5] in 1975 for the treatment of superficial bladder cancer, and since then, after numerous studies, it was confirmed that PDT is an effective method for the treatment of bladder cancer. Since 1993, PDT has gradually become an important tool in the treatment of bladder tumors.
1.1 Basic principles of photodynamic therapy and photosensitizers
After the body receives the photosensitizer for a certain time, the tumor tissues take up and store more photosensitizer, which is irradiated by light of specific wavelengths and undergoes photochemical reactions with the participation of oxygen in biological tissues, generating singlet oxygen and/or free radicals, which destroy a variety of biological macromolecules in tissues and cells and eventually cause the death of tumor cells for therapeutic purposes [6].
Photodynamic therapy has three essential conditions: photosensitizer, light and oxygen [7,8]. Among them, the photosensitizer is the most important factor, which is the basis for performing PDT and the bottleneck that limits the development of photodynamics. Photosensitizers for photodynamic diagnosis and treatment must be able to accumulate specifically in tumor tissues and not or less in normal tissues, thus being able to distinguish tumors from normal tissues. The ideal photosensitizer should meet the following conditions [9]: 1), a strong absorption peak in the red region of visible light (wavelength > 630 nm); 2), a high rate of triplet-state quantum production; 3), a high rate of quantum production of singlet-state oxygen; 4), low dark toxicity; 5), selective retention in cancerous tissues and no or little absorption for healthy tissues, especially skin; 6), easy synthesis in large quantities , simple formulation, and easy to preserve; 7), according to the pharmacokinetic requirements, the excess drug can be excreted from the body quickly.
At present, photosensitizer research mainly experienced three generations: the first generation of photosensitizers for hematoporphyrin derivatives (such as HpD, Porphines, etc.), must be administered intravenously or orally, poor targeting, slow excretion, prone to phototoxic reactions, after the drug must be a long time to avoid light, has been largely eliminated. After the eighties, the second generation of photosensitizer development research is developing rapidly, in photosensitive activity, absorption spectrum and tissue selectivity than the first generation of photosensitizers have been greatly improved. The second generation photosensitizers are derivatives of porphyrins, such as benzoporphyrin derivative monocyclic acid A (BPD-MA), hypocrellin, hypericin, 5-aminoacetoacetic acid (5-ALA), etc. Although 5-ALA bladder perfusion can avoid the appearance of side effects such as skin photosensitivity reactions, there are still poor targeting, slow cell Although 5-ALA bladder perfusion can avoid side effects such as skin photosensitivity, it still has disadvantages such as poor targeting and slow uptake, and the drug must act with the bladder mucosa for more than 4 hours to produce therapeutic effects. Moreover, the synthesis process of BPD-MA and 5-ALA is complicated, the yield is low, and the cost is high, so the price is expensive. Chlorophyll-based photosensitizers are new types of photosensitizers, which are not available at home and abroad. Some research institutions have used chlorophyll derivatives (extract of Chinese silkworm sand) for oral administration for clinical and basic studies of PDT treatment, and obtained certain efficacy and less skin phototoxicity [8]. The third generation of drugs, which are linked to monoclonal antibodies or antisense oligonucleotides, are “biological missile” type drugs with higher selectivity and specificity, and are still under laboratory design and development.
In conclusion, there is still a lack of ideal photosensitizers with good targeting, strong photosensitivity, fast cellular uptake, and simple extraction and synthesis at home and abroad. Because of this, the enthusiasm for research on photodynamic therapy at home and abroad has been somewhat dampened after 2006, but it still cannot conceal the promising future of photodynamic therapy.
Photodynamics for the diagnosis and treatment of bladder cancer
In vitro experiments have confirmed:The precipitation of protoporphyrin IX is associated with the proliferation of cells [10]. After bladder perfusion with a photosensitizer, protoporphyrin IX accumulated highly selectively in the nascent bladder mucosal tissue, with a concentration ratio of 17:1 of protoporphyrin IX precipitation in normal mucosal tissue. after laser irradiation, the malignant parts of the bladder mucosa fluoresced red, in contrast to the blue fluorescence of normal bladder mucosa. Therefore, fluorescence cystoscopy can detect microscopic lesions that are not detected by ordinary cystoscopy.
Theoretically, PDT is a “targeted, cellular, microscopic killing effect”, which is more suitable for the “multicentric occurrence” and “high recurrence” of bladder cancer in clinical practice. With the rapid development of laser, fiber optic and endoscopic technologies, photodynamic diagnosis and treatment of bladder cancer has great intracavitary advantages and a bright future. Especially for “precancerous lesions, very early stage cancer, recurrent cancer and carcinoma in situ (Tis)”, although clinically it is difficult to achieve effective treatment, PDT can even achieve curative effect with low recurrence rate [11,12]. In addition, PDT also has palliative efficacy for intermediate and advanced cancer. Clinically, PDT is mainly applied to patients with refractory bladder cancer and carcinoma in situ whose tumors have repeatedly recurred, who have failed to respond to chemotherapy and immunotherapy, or who cannot tolerate surgery, or are unwilling to undergo surgery [13].
Ray ER [14] et al. reported using fluorescence cystoscopy in 18 patients with postoperative bladder tumors, and the detection rate of fluorescence cystoscopy was 97.8% compared to the detection rate of 69.6% with plain cystoscopy. The results showed that photodynamic diagnosis using fluorescence cystoscopy has a higher detection rate and can be an important method for postoperative follow-up of tumors [14,15].Nseyo et al [16] summarized 13 years of experience in treating 58 cases of bladder cancer, and PDT was effective in 84.2% (48/58) of patients. He concluded that PDT should be performed immediately after failure of conventional treatment for superficial bladder cancer, BCG or chemotherapy, and PDT can be a second-line treatment option for such patients.
2 .Nanomodification technology and photodynamic effects
2.1 Nanotechnology and nanomedicine
The effectiveness of PDT for bladder cancer is clearly related to the photosensitizer used. The desired tumor-killing effect can only be produced if the photosensitizer is concentrated in bladder cancer cells in a highly efficient and targeted manner. An important factor currently limiting the clinical application of PDT is the lack of an ideal photosensitizer. The rapid development of nanotechnology has provided ideas to solve the above-mentioned challenges. Nanodevices with a length of only 1-100 nm are able to freely enter and exit human cells and have the advantages of small size, biocompatibility and organ-targeting ability compared with previous diagnostic and therapeutic approaches [17]. The concept of using nanotechnology in medical research and clinical practice is known as nanomedicine, a concept first proposed by the famous Nobel laureate Richard Feynman. Tiny nanorobots and nanodevices can be used to provide faster and more accurate and reliable diagnostic and therapeutic approaches [18]. Nanoparticles loaded with antibodies, collagen and micromolecules have been used for early diagnosis of tumors [19]. In addition, nano-encapsulated antitumor drugs or gene drugs can be used for targeted antitumor therapy and to reduce the toxic side effects of drugs [20-22].
2.2 Nanomodification and drug-targeting effects
The traditional routes of administration of oral and injectable drugs alter the pharmacokinetic parameters and do not allow targeted drug delivery. In addition, genetic polymorphisms, beyond the efflux pump and drug resistance, reduce the efficacy of the drug. The use of nanotechnology-mediated drug delivery can overcome these drawbacks and allows for targeted drug delivery, thus reducing the toxic effects of the drug [23]. Nanoparticles used for drug delivery, including liposomes, gold nanoparticles, magnetic nanoparticles and carbon nanotubes. Targeted drugs, nucleic acids and other molecules synthesized using nanoparticles are the focus of current research and development. A variety of nanoparticles can enable tumor-targeted drug delivery [24]. Tumor tissues differ from normal tissues in that they have endothelial cell pore sizes up to 200 nm-1.2 um, and nanoparticles pass through large pore sizes and accumulate in tumor tissues [25]. Drug-containing nanomicrospheres with surface modification combined with long circulation times for intravenous drug delivery make transmucosal delivery of water-soluble biomolecular drugs and targeted drug delivery to specific tissues or cells possible. The vascular system in tumor sites has higher permeability than normal sites (EPR effect), and with the guarantee of long circulation time, nano-drug carriers can take full advantage of the above effect to enrich in tumor sites and achieve the effect of “passive targeting” drug delivery, which not only improves the tumor targeting and cellular uptake rate of drugs, but also reduces their systemic toxicity [26,26 Hu Y [28] et al. used nano-microspheres wrapped with paclitaxel to kill HepG2 cells in vitro and showed that the microspheres had better drug uptake and cell killing effects.
2.3 Nanomodified photosensitizers-photosensitive nanomicrospheres
The use of nanotechnology to modify photosensitized nanoparticles is a new direction in the development of photosensitizers. 2007, Vargas et al [29] used nanospheres to encapsulate the photosensitizer porphyrin and initially showed better cellular uptake and photodynamic killing in in vitro experiments. At present, the international research on “photosensitive nanomicrospheres for photodynamic therapy of tumors” is in the nascent stage. Some scholars predict that nanotechnology will set off a new wave of photodynamic therapy research, and photosensitive nanomicrospheres will have the most promising clinical applications [30].
3 , Conclusion and Prospect
Nanotechnology has been used to encapsulate antitumor drugs, and experiments have shown that nanomicrospheres can improve drug loading efficiency and reduce drug toxicities. The US FDA has approved the marketing of albumin-bound paclitaxel nanoparticle injection suspension (paclitaxel , ABI-007) for breast cancer recurring after failed combination chemotherapy or within 6 months of adjuvant chemotherapy in metastatic breast cancer [31]. It is conceivable that the targeted delivery and controlled release of photosensitizers could be better advanced by advances in nanotechnology and nanomaterials. Photosensitive nanomicrospheres could well become a novel photosensitizer to meet clinical needs. Photosensitive nanomicrospheres will most likely be used for clinical treatment of bladder cancer in situ (Tis), reduction of postoperative recurrence of bladder cancer, and palliative treatment of advanced bladder cancer.